Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging

Abstract

Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [11C]domperidone and [11C]metoclopramide. In P-gp-overexpressing cells, the IC50 of tariquidar, a potent P-gp inhibitor, was drastically different using [11C]domperidone (221 nM [198–248 nM]) or [11C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [11C]domperidone compared with [11C]metoclopramide (p brain) of [11C]metoclopramide was 2.4-fold higher compared with [11C]domperidone (p brain/AUCplasma). The maximal increase in the brain exposure (2.9-fold, p p 11C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [11C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB.

Keywords

• ATP-binding cassette
• drug–drug interaction
• membrane transporter
• neuropharmacology
• pharmacokinetics
• PET imaging